The Her2 (EGFR2, ErbB2) receptor tyrosine kinase is a member of the epidermal growth factor receptor (EGFR) family of transmembrane receptors. Her2 is overexpressed in approximately 20-25% of primary breast cancers (Slamon et al., Science 244:707-712, 1989). Overexpression of Her2 has been implicated in the aggressive growth and poor clinical outcome associated with Her2-positive breast tumors (Slamon et al., Science 235:177-182, 1987).
Her2-positive breast cancer is commonly treated with trastuzumab (Herceptin®), a humanized IgG1 monoclonal antibody that specifically binds the extracellular domain of human Her2. Trastuzumab kills Her2-expressing cancer cells by mediating antibody-dependent cellular cytotoxicity (ADCC). However, a number of patients treated with trastuzumab do not respond to treatment, or stop responding after a period of time. Furthermore, the majority of patients with tumors that respond to trastuzumab treatment, ultimately progress. Therefore, there is a clinical need to develop further therapies for the treatment of Her2-positive cancer.
A promising form of therapy for cancer involves the use of antibody-drug conjugates (ADCs), which are capable of specifically targeting a cytotoxic agent to malignant cells without causing significant adverse effects on normal tissues (Teicher and Doroshow, N Engl J Med 367(19):1847-1848, 2012). ADCs are comprised of a tumor antigen-specific monoclonal antibody conjugated to a cytotoxic drug, such as an anti-microtubule agent (Bander, Clinical Advances in Hematology & Oncology 10(8; suppl 10):3-7, 2012). The ideal ADC utilizes an antibody that specifically binds a tumor antigen with reasonable affinity, and exhibits limited or no immunogenicity. The linker should be stable in the circulation so that the cytotoxic agent is not released systemically where it can contact non-target cells. In addition, the linker should maintain attachment of the antibody to the cytotoxic agent until the ADC reaches the tumor and is internalized. Common cytotoxic agents for ADCs include anti-microtubule agents, such as maytansinoids and auristatins (e.g., auristatin E and auristatin F), and pyrrolobenzodiazepines (PDBs) (Bander, Clinical Advances in Hematology & Oncology 10(8; suppl 10):3-7, 2012).